-
CNS Spectrums May 2010Attention-deficit/hyperactivity disorder (ADHD) is a highly genetic neuropsychiatric disorder that can cause impairment at school, work, home, and in social... (Review)
Review
Attention-deficit/hyperactivity disorder (ADHD) is a highly genetic neuropsychiatric disorder that can cause impairment at school, work, home, and in social relationships. Once considered a childhood disorder, as many as 65% of children with ADHD continue to exhibit symptoms into adulthood. While a mainstay of ADHD patient care, immediate-release stimulant use has been constrained by concerns about safety, tolerability, and issues related to nonmedical use and abuse. These concerns have prompted interest in developing modified versions or new delivery systems for stimulants. Prodrugs have been used in pharmaceutical development to optimize delivery of an active drug or to minimize toxicity. Prodrugs are pharmacologically inactive compounds that require in vivo conversion to release therapeutically active medications. Lisdexamfetamine dimesylate (LDX) is an inactive, water-soluble prodrug in which d-amphetamine is bonded to l-lysine, a naturally occurring amino acid. After oral ingestion, LDX is metabolized into l-lysine and active d-amphetamine. This review of LDX presents the efficacy, safety, and pharmacokinetic profile of this novel stimulant medication, and is intended to help clinicians understand its role in treating children and adults with ADHD.
Topics: Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Dextroamphetamine; Humans; Lisdexamfetamine Dimesylate; Prodrugs; Treatment Outcome
PubMed: 20448522
DOI: 10.1017/s1092852900027541 -
Molecules (Basel, Switzerland) Oct 2014The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug... (Comparative Study)
Comparative Study
The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.
Topics: Administration, Oral; Animals; Biological Transport; Drug Delivery Systems; Drug Design; Humans; Membrane Transport Proteins; Permeability; Prodrugs
PubMed: 25317578
DOI: 10.3390/molecules191016489 -
Dalton Transactions (Cambridge, England... Feb 2022In this work, we present the first study about the interactions of mitochondria-damaging Pt(IV) prodrugs with cytochrome c. We synthesized a cisplatin-based Pt(IV)...
In this work, we present the first study about the interactions of mitochondria-damaging Pt(IV) prodrugs with cytochrome c. We synthesized a cisplatin-based Pt(IV) prodrug bearing a lipophilic hydrocarbon tail and anionic dansyl head group. The amphiphilic structure facilitates its accumulation in the mitochondria of cancer cells, which was validated using graphite furnace atomic absorption spectroscopy (GFAAS) and fluorescence imaging. Accordingly, this Pt(IV) prodrug is able to trigger mitochondrial damage and apoptosis. Overall, the Pt(IV) prodrug exhibits superior therapeutic effects against a panel of human cancer cells compared to cisplatin. It also overcomes drug resistance in ovarian cancer. Notably, HPLC analysis indicates that cytochrome c accelerates reduction (or activation) of the Pt(IV) prodrug in the presence of the electron donor nicotinamide adenine dinucleotide (NADH). More interestingly, additional studies indicate that cytochrome c was platinated by the reduced product of Pt(IV) prodrugs, and that empowers the proapoptotic peroxidase activity.
Topics: Antineoplastic Agents; Cell Line, Tumor; Chromatography, High Pressure Liquid; Cytochromes c; Humans; Mitochondria; Platinum Compounds; Prodrugs
PubMed: 35029256
DOI: 10.1039/d1dt03875c -
Science Advances May 2020CO gas molecule not only could selectively kill cancer cells but also exhibits limited anticancer efficacy because of the lack of active tumor-targeted accumulation...
CO gas molecule not only could selectively kill cancer cells but also exhibits limited anticancer efficacy because of the lack of active tumor-targeted accumulation capability. In this work, a multistage assembly/disassembly strategy is developed to construct a new intelligent nanomedicine by encapsulating a mitochondria-targeted and intramitochondrial microenvironment-responsive prodrug (FeCO-TPP) within mesoporous silica nanoparticle that is further coated with hyaluronic acid by step-by-step electrostatic assembly, realizing tumor tissue-cell-mitochondria-targeted multistage delivery and controlled release of CO in a step-by-step disassembly way. Multistage targeted delivery and controlled release of CO involve (i) the passive tumor tissue-targeted nanomedicine delivery, (ii) the active tumor cell-targeted nanomedicine delivery, (iii) the acid-responsive prodrug release, (iv) the mitochondria-targeted prodrug delivery, and (v) the ROS-responsive CO release. The developed nanomedicine has effectively augmented the efficacy and safety of CO therapy of cancer both in vitro and in vivo. The proposed multistage assembly/disassembly strategy opens a new window for targeted CO therapy.
Topics: Cell Line, Tumor; Delayed-Action Preparations; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Prodrugs; Silicon Dioxide; Tumor Microenvironment
PubMed: 32440551
DOI: 10.1126/sciadv.aba1362 -
Signal Transduction and Targeted Therapy Jan 2022
Topics: Cell Hypoxia; Cell Line, Tumor; Humans; Immunoconjugates; Prodrugs
PubMed: 35058439
DOI: 10.1038/s41392-021-00833-8 -
Drug Metabolism and Pharmacokinetics Jun 2006Human carboxylesterase 1 (hCE-1, CES1A1, HU1) and carboxylesterase 2 (hCE-2, hiCE, HU3) are a serine esterase involved in both drug metabolism and activation. Although... (Review)
Review
Human carboxylesterase 1 (hCE-1, CES1A1, HU1) and carboxylesterase 2 (hCE-2, hiCE, HU3) are a serine esterase involved in both drug metabolism and activation. Although both hCE-1 and hCE-2 are present in several organs, the hydrolase activity of liver and small intestine is predominantly attributed to hCE-1 and hCE-2, respectively. The substrate specificity of hCE-1 and hCE-2 is significantly different. hCE-1 mainly hydrolyzes a substrate with a small alcohol group and large acyl group, but its wide active pocket sometimes allows it to act on structurally distinct compounds of either large or small alcohol moiety. In contrast, hCE-2 recognizes a substrate with a large alcohol group and small acyl group, and its substrate specificity may be restricted by a capability of acyl-hCE-2 conjugate formation due to the presence of conformational interference in the active pocket. Furthermore, hCE-1 shows high transesterification activity, especially with hydrophobic alcohol, but negligible for hCE-2. Transesterification may be a reason for the substrate specificity of hCE-1 that hardly hydrolyzes a substrate with hydrophobic alcohol group, because transesterification can progress at the same time when a compound is hydrolyzed by hCE-1. From the standpoint of drug absorption, the intestinal hydrolysis by CES during drug absorption is evaluated in rat intestine and Caco2-cell line. The rat in situ single-pass perfusion shows markedly extensive hydrolysis in the intestinal mucosa. Since the hydrolyzed products are present at higher concentration in the epithelial cells rather than blood vessels and intestinal lumen, hydrolysates are transported by a specific efflux transporter and passive diffusion according to pH-partition. The expression pattern of CES in Caco-2 cell monolayer, a useful in vitro model for rapid screening of human intestinal drug absorption, is completely different from that in human small intestine but very similar to human liver that expresses a much higher level of hCE-1 and lower level of hCE-2. Therefore, the prediction of human intestinal absorption using Caco-2 cell monolayers should be carefully monitored in the case of ester and amide-containing drugs such as prodrugs. Further experimentation for an understanding of detailed substrate specificity for CES and development of in vitro evaluation systems for absorption of prodrug and its hydrolysates will help us to design the ideal prodrug.
Topics: Animals; Carboxylic Ester Hydrolases; Catalysis; Drug Design; Humans; Intestinal Absorption; Isoenzymes; Prodrugs
PubMed: 16858120
DOI: 10.2133/dmpk.21.173 -
Indian Journal of Pharmacology 2015To develop an amino acid prodrug of acetaminophen with comparable therapeutic profile and less hepatotoxicity than acetaminophen.
OBJECTIVE
To develop an amino acid prodrug of acetaminophen with comparable therapeutic profile and less hepatotoxicity than acetaminophen.
MATERIALS AND METHODS
Acetaminophen prodrug was synthesized by esterification between the carboxyl group of amino acid glycine and hydroxyl group of acetaminophen. Analgesic, antipyretic, ulcer healing, and hepatotoxic activities were performed on Wistar rats in this study.
RESULTS
Prodrug showed a 44% inhibition in writhings as compared to 53.3% of acetaminophen. Acetaminophen also offered highest antipyretic activity. Prodrug showed gastroprotective and hepatoprotective effects as it reduced the gastric lesions by 32.1% (P < 0.01) and significantly prevented the rise in liver enzymes (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and bilirubin). The most notable effect of prodrug was in preventing the depletion of hepatic glutathione (GSH), which is reduced by acetaminophen.
CONCLUSION
Prodrug showed hepatoprotective and gastroprotective effects, although the therapeutic efficacy was compromised. Prodrug was successful in preventing a decrease in GSH, thereby exhibiting promising results in the field of prodrug designing to avoid the toxic effects of acetaminophen.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Antipyretics; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Fever; Glycine; Liver Function Tests; Male; Mice, Inbred BALB C; Molecular Structure; Pain; Prodrugs; Rats, Wistar
PubMed: 25878383
DOI: 10.4103/0253-7613.153431 -
International Journal of Nanomedicine 2019A palmitoylated prodrug of emtricitabine (FTC) was synthesized to extend the drug's half-life, antiretroviral activities and biodistribution.
PURPOSE
A palmitoylated prodrug of emtricitabine (FTC) was synthesized to extend the drug's half-life, antiretroviral activities and biodistribution.
METHODS
A modified FTC prodrug (MFTC) was synthesized by palmitoyl chloride esterification. MFTC's chemical structure was evaluated by nuclear magnetic resonance. The created hydrophobic prodrug nanocrystals were encased into a poloxamer surfactant and the pharmacokinetics (PK), biodistribution and antiretroviral activities of the nanoformulation (NMFTC) were assessed. The conversion of MFTC to FTC triphosphates was evaluated.
RESULTS
MFTC coated with poloxamer formed stable nanocrystals (NMFTC). NMFTC demonstrated an average particle size, polydispersity index and zeta potential of 350 nm, 0.24 and -20 mV, respectively. Drug encapsulation efficiency was 90%. NMFTC was readily taken up by human monocyte-derived macrophages yielding readily detected intracellular FTC triphosphates and an extended PK profile.
CONCLUSION
NMFTC shows improved antiretroviral activities over native FTC. This is coordinate with its extended apparent half-life. The work represents an incremental advance in the development of a long-acting FTC formulation.
Topics: Animals; Anti-Retroviral Agents; Carbon-13 Magnetic Resonance Spectroscopy; Drug Compounding; Emtricitabine; Humans; Kinetics; Macrophages; Male; Nanoparticles; Prodrugs; Proton Magnetic Resonance Spectroscopy; Rats, Sprague-Dawley
PubMed: 31496683
DOI: 10.2147/IJN.S215447 -
Angewandte Chemie (International Ed. in... Feb 2021Prodrug and drug delivery systems are two effective strategies for improving the selectivity of chemotherapeutics. Molecularly imprinted polymers (MIPs) have emerged as...
Prodrug and drug delivery systems are two effective strategies for improving the selectivity of chemotherapeutics. Molecularly imprinted polymers (MIPs) have emerged as promising carriers in targeted drug delivery for cancer treatment, but they have not yet been integrated with the prodrug strategy. Reported here is an MIP-based smart prodrug delivery system for specific targeting, prolonged retention time, and tumor microenvironment-triggered release. 5'-Deoxy-5-fluorocytidine (DFCR) and sialic acid (SA) were used as a prodrug and a marker for tumor targeting, respectively. Their co-imprinted nanoparticles were prepared as a smart carrier. Prodrug-loaded MIP specifically and sustainably accumulated at the tumor site and then gradually released. Unlike conventional prodrug designs, which often require in-liver bioconversion, this MIP-based prodrug delivery is liver-independent but tumor-dependent. Thus, this study opens new access to the development of smart prodrug delivery nanoplatforms.
Topics: Drug Delivery Systems; Humans; Molecularly Imprinted Polymers; Prodrugs; Tumor Microenvironment
PubMed: 33078504
DOI: 10.1002/anie.202012956 -
ChemMedChem Dec 2021The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In... (Review)
Review
The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the "mutual prodrug" approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad-spectrum chemotherapeutics available for clinical use today, 5-fluorouracil (5-FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5-FU-based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Drug Synergism; Enzyme Inhibitors; Fluorouracil; Humans; Neoplasms; Prodrugs
PubMed: 34415107
DOI: 10.1002/cmdc.202100473